tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation
Authors: Xinyi Hu, Jiayan Shen, Tao Wang, Mengyang Liu
Journal: Hepatology (2023)

To the editor, We followed with interest the article by Ma et al1 reporting that DRP1 deficiency led to mitochondrial dysfunction and increased mitochondrial DNA (mtDNA) release, resulting in activation of the cGAS-STING signaling pathway and exacerbation of alcohol-induced liver inflammatory injury. However, we believe there are some crucial aspects concerning the pathological mechanism of cGAS-STING signaling–mediated immune response that require further clarification and discussion. First, the study reported that cGAS-STING signaling is activated, and the expression levels of STING, p-TBK1, and p-IRF3 involved in this pathway were increased in patients with alcoholic hepatitis. Nevertheless, alcohol feeding did not activate the cGAS-STING pathway in mice regardless of DRP1 deficiency. In addition, their downstream gene and serum mtDNA levels were also not affected, and loss of DRP1 even caused some genes' expression levels to be markedly reduced by alcohol intake. However, there is no clear explanation regarding these contradictory results between patient and mice. Therefore, it is necessary to reinspect the reliability of the present experimental model. Second, the current study only detected mtDNA accumulation in mice serum and hepatocyte cytoplasm, while the level of mtDNA released by hepatocytes into the extracellular space was not determined. Of note, previous studies have demonstrated that stress-induced cytosolic leakage of mtDNA plays a crucial role in both intracellular and intercellular activation of cGAS-STING signaling.2 Thus, apart from confirming cytoplasmic mtDNA accumulation, it is also important to investigate the extracellular release level of alcohol-induced hepatocellular mtDNA to further add credibility to the results of intercellular cGAS-STING activation. Third, in this research, there is no clear conclusion whether cGAS-STING is activated in hepatocyte or macrophage/KCs. The investigators only confirmed that cGAS was mainly expressed in the nucleus of these cells. In Supplemental Figure S11B of Ma et al,1 it seems that nonparenchymal cell and KCs are the major cell types in cGAS-STING signaling activation, since this pathway-related protein can be hardly detected in hepatocytes. However, a previous study showed that hepatocyte was the primary cell type responsible for the alcohol-induced cGAS-STING activation.3 Therefore, the degree of contribution of liver parenchymal cells, macrophages, and nonparenchymal cells to DRP1 deficiency or alcohol-induced cGAS-STING activation should be further clarified. In conclusion, this study provides a new insight into the understanding of mitochondrial dynamics in the innate immune response–associated pathogenesis of alcohol-associated liver disease. However, further studies are needed regarding the above issues to solidify the current conclusions.
Chemotherapy with or without selective internal radiation therapy for intrahepatic cholangiocarcinoma: Data from clinical trials
Authors: Julien Edeline, John Bridgewater, Boris Campillo-Gimenez, Estelle Neveu, Jean-Marc Phelip, Cindy Neuzillet, Karim Boudjema, Yan Rolland, Juan W. Valle, Etienne Garin, David Malka, Angela Lamarca
Journal: Hepatology (2023)

Backgound and Aims: In advanced, liver-only intrahepatic cholangiocarcinoma (iCCA), selective internal radiation therapy (SIRT) has been suggested as promising in nonrandomized studies. We aimed to compare data from patients with advanced, liver-only iCCA treated in the first line in clinical trials with either chemotherapy alone or the combination with SIRT. Approach and Results: We collected individual patients’ data from the ABC-01, ABC-02, ABC-03, BINGO, AMEBICA, and MISPHEC prospective trials. Data from patients with liver-only iCCA treated in chemotherapy-only arms of the first 5 trials were compared with data from patients treated with SIRT and chemotherapy in MISPHEC. Emulated target trial paradigm and Inverse Probability of Treatment Weighting (IPTW methods) using the propensity score were used to minimize biases. We compared 41 patients treated with the combination with 73 patients treated with chemotherapy alone, the main analysis being in 43 patients treated with cisplatin-gemcitabine or gemcitabine-oxaliplatin. After weighting, overall survival was significantly higher in patients treated with SIRT: median 21.7 months (95% CI: 14.1; not reached) versus 15.9 months(95% CI: 9.8; 18.9), HR = 0.59 (95% CI: 0.34; 0.99), p = 0.049. Progression-free survival was significantly improved: median 14.3 months (95% CI: 7.8; not reached) versus 8.4 months (95% CI: 5.9; 12.1), HR = 0.52 (95% CI: 0.31; 0.89), p &lt; 0.001. Results were confirmed in most sensitivity analyses. Conclusions: This analysis derived from prospective clinical trials suggests that SIRT combined with chemotherapy might improve outcomes over chemotherapy alone in patients with advanced, liver-only iCCA. Randomized controlled evidence is needed to confirm these findings.
Anti-TNF Agents and New Biological Agents (Vedolizumab and Ustekinumab) in the Prevention and Treatment of Postoperative Recurrence After Surgery in Crohn’s Disease
Authors: Javier P. Gisbert, María Chaparro
Journal: Drugs (2023)

Surgery for Crohn's disease (CD) is not curative, as postoperative recurrence (POR) after ileocolonic resection is the rule in the absence of prophylactic treatment. In the present article, we critically review available data on the role of anti-tumour necrosis factor (TNF) agents and new biologics (including vedolizumab and ustekinumab) in the prevention and treatment of POR after surgery in CD. Several studies (summarised in various meta-analyses) have confirmed the efficacy of anti-TNFs in the prevention of POR. We identified 37 studies, including 1863 CD patients, with mean endoscopic POR at 6–12 months of 29%. Only few randomised controlled trials (RCTs) have directly compared thiopurines and anti-TNFs, with controversial results, although the superiority of the latter is supported by several meta-analyses. Infliximab and adalimumab seem equally effective. The combination of anti-TNFs and immunosuppressives should be considered in patients previously exposed to anti-TNFs. Several studies have shown that anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. In fact, the use of the same anti-TNF before and after surgery might be effective for the prevention of POR. Prophylactic anti-TNF treatment, once started, should be continued long term. Anti-TNFs are also effective for the treatment of established POR. Retreatment with anti-TNFs for POR is a valid strategy even after their preoperative failure. In six studies (including 156 patients) evaluating vedolizumab, mean endoscopic POR at 6–12 months was 41%. The non-randomised comparison of anti-TNFs and vedolizumab has provided controversial results. One placebo-controlled RCT confirmed that vedolizumab is quite effective in preventing POR in CD patients with increased risk of recurrence. Seven studies (including 162 patients) evaluated ustekinumab, with a mean endoscopic POR at 6–12 months of 41%. The comparative efficacy of ustekinumab and anti-TNFs is still unclear. Ustekinumab and vedolizumab seem to be equally effective, although the experience is very limited. In conclusion, to date, anti-TNFs are the most effective agents in preventing and treating POR in CD. Anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. Vedolizumab seems to be quite effective in the prevention of POR in patients with increased risk of recurrence. Ustekinumab is probably also effective in the postoperative setting, although the comparative efficacy with anti-TNFs or vedolizumab is still unclear.
Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists
Authors: Rasha Alhiary, Aaron S. Kesselheim, Sarah Gabriele, Reed F. Beall, S. Sean Tu, William B. Feldman
Journal: JAMA (2023)

Glucagon-like peptide 1 (GLP-1) receptor agonists were first approved for the treatment of type 2 diabetes in 2005. Demand for these drugs has increased rapidly in recent years, as indications have expanded, but they remain expensive.
Myeloid-specific ablation of Basp1 ameliorates diet-induced NASH in mice by attenuating pro-inflammatory signaling
Authors: Ziyi Meng, Linkang Zhou, Sungki Hong, Xiaoxue Qiu, Zhimin Chen, Tongyu Liu, Ken Inoki, Jiandie D. Lin
Journal: Hepatology (2023)

Background and Aims: NASH represents a severe stage of fatty liver disease characterized by hepatocyte injury, inflammation, and liver fibrosis. Myeloid-derived innate immune cells, such as macrophages and dendritic cells, play an important role in host defense and disease pathogenesis. Despite this, the nature of transcriptomic reprogramming of myeloid cells in NASH liver and its contribution to disease progression remain incompletely defined. Approach and Results: In this study, we performed bulk and single-cell RNA sequencing (sc-RNA seq) analysis to delineate the landscape of macrophage and dendritic cell transcriptomes in healthy and NASH livers. Our analysis uncovered cell type-specific patterns of transcriptomic reprogramming on diet-induced NASH. We identified brain-abundant membrane-attached signal protein 1 (Basp1) as a myeloid-enriched gene that is markedly induced in mouse and human NASH liver. Myeloid-specific inactivation of Basp1 attenuates the severity of diet-induced NASH pathologies, as shown by reduced hepatocyte injury and liver fibrosis in mice. Mechanistically, cultured macrophages lacking Basp1 exhibited a diminished response to pro-inflammatory stimuli, impaired NLRP3 inflammasome activation, and reduced cytokine secretion. Conclusions: Together, these findings uncover Basp1 as a critical regulator of myeloid inflammatory signaling that underlies NASH pathogenesis.
Evidence-based consensus guidelines for the diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and X-linked protoporphyria
Authors: Cynthia Levy, Amy K. Dickey, Bruce Wang, Manish Thapar, Hetanshi Naik, Siobán B. Keel, Behnam Saberi, Simon W. Beaven, Sean R. Rudnick, Sarina B. Elmariah, Angelika L. Erwin, Robert J. Goddu, Karli Hedstrom, Rebecca Karp Leaf, Mohamed Kazamel, Marshall Mazepa, Lisa Liang Philpotts, John Quigley, Haya Raef, Jonathan Ungar, Karl E. Anderson, Manisha Balwani
Journal: Hepatology (2023)

Levy, Cynthia; Dickey, Amy K.; Wang, Bruce; Thapar, Manish; Naik, Hetanshi; Keel, Siobán B.; Saberi, Behnam; Beaven, Simon W.; Rudnick, Sean R.; Elmariah, Sarina B.; Erwin, Angelika L.; Goddu, Robert J.; Hedstrom, Karli; Leaf, Rebecca Karp; Kazamel, Mohamed; Mazepa, Marshall; Philpotts, Lisa Liang; Quigley, John; Raef, Haya; Ungar, Jonathan; Anderson, Karl E.; Balwani, Manisha; on behalf of the Porphyrias Consortium of the Rare Diseases Clinical Network. Author Information
Incidence of Neonatal Seizures in China Based on Electroencephalogram Monitoring in Neonatal Neurocritical Care Units
Authors: Kai Yan, Guoqiang Cheng, Wei Zhou, Feifan Xiao, Chongfan Zhang, Laishuan Wang, Peng Zhang, Chunmei Lu, Yanting Kong, Xinhua Wang, Yuanfeng Zhou, Weineng Lu, Juan Tang, Xiaoyan Song, Qiufen Wei, Danhua Meng, Liping Yao, Deyi Zhuang, Liuhong Qu, Qinghuo Xu, Zhaoqing Yin, Le Su, Jing Wan, Yuan Si, Kazumichi Fujioka, Michele Mussap, Shibani Kanungo, Vineet Bhandari, Weimin Huang, Xinnian Pan, Wenhao Zhou, Yuan Shi, Changyi Yang, Huaping Zhu, Mingyan Hei, Xing Feng, Xin Ding, Zhenlang Lin, Shangqin Chen, Lizhong Du
Journal: JAMA Network Open (2023)

Importance Neonatal seizures pose a significant challenge in critical care, and continuous video electroencephalography (cEEG) monitoring holds promise for early detection of seizures. However, large-scale data on the incidence of neonatal seizures and monitoring systems in China are lacking. Objectives To determine the incidence of neonatal seizures in infants with high risk in China. Design, Setting, and Participants A large, cross-sectional multicenter study was conducted from January 2017 to December 2018 in the neonatal intensive care units (NICUs) of 7 tertiary medical centers in China. Neonates with high risk were included, and cEEG monitoring was conducted. Data were collected between January 1, 2017, and January 31, 2020. The data were analyzed between January 2021 and January 2022. Main Outcomes and Measures The incidence of neonatal seizures, categorized by etiology, and seizure burden. Results A total of 20 310 neonates with high risk were included (10 495 [51.7%] male; mean [SD] postmenstrual age, 37.7 [3.7] weeks), and seizures were observed in 3423 infants (16.9%). The highest proportion of seizures was attributed to acute neonatal encephalopathy (1448 [42.3%]). The incidence of seizures decreased with postmenstrual age and birth weight, with the highest occurrence observed in neonates with postmenstrual age of less than 28 weeks (237 of 879 [27.0%]) or birth weight of less than 1.0 kg (269 of 914 [29.4%]). Preterm infants had a higher proportion of moderate and severe seizure burdens compared with full-term infants (moderate severity: 248 of 1199 [20.7%] vs 454 of 2224 [20.4%]), but no significant differences were observed in etiology. Seizure burden was highest with genetic syndromes (49 of 188 [26.1%]), central nervous system malformations (33 of 127 [26.0%]), and inborn errors of metabolism (27 of 113 [23.9%]). During hospitalization, 7.8% of neonates with seizures died (267 neonates), with 81.3% of these cases having a moderate or severe seizure burden (217 neonates). Mortality was generally higher in preterm vs full-term infants (98 of 1199 [8.2%] vs 169 of 2224 [7.6%]) and increased with the severity of seizure burden (217 of 267 neonates with moderate or severe burden [81.3%]). Conclusions and Relevance This cross-sectional study of neonatal seizures underscores the substantial burden seizures pose to high-risk infants with brain injury in China, particularly those who are born prematurely or who have congenital conditions.
“Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.” S.M. Kawut, M.J. Krowka, K.A. Forde, N. Al-Naamani, K.L. Krok, M. Patel, C.R. Bartoli, M. Doyle, J. Moutchia, G. Lin, J.K. Oh, C.D. Mottram, P.D. Scanlon and M.B. Fallon for the Pulmonary Vascular Complications of Liver Disease Study Group.<i>Eur Respir J</i>2022; 60: 2102304.
Journal: European Respiratory Journal (2023)

In the Materials and methods, Data collection and variables subsection of this manuscript, the formulae used to calculate the Model for End-Stage Liver Disease-Na score were presented incorrectly as:"The Model for End-Stage Liver Disease (MELD-Na) score was calculated using the following formulae: MELD=10×((0.957×ln(creatinine))+(0.378×ln(bilirubin))+(1.12×ln(international normalised ratio)))+6.43 and MELD-Na=MELD+(0.32×(137-Na))-(0.033×MELD×(137-Na)."The correct version is:"The Model for End-Stage Liver Disease (MELD-Na) score was calculated using the following formulae: MELD=10×((0.957×ln(creatinine))+(0.378×ln(bilirubin))+(1.12×ln(international normalised ratio)))+0.643 and MELD-Na=MELD+(1.32×(137-Na))-(0.033×MELD×(137-Na))."The correct formulae were used in the data analysis so that the results stand as presented.
B and T cell responses to the BNT162b2 COVID-19 mRNA vaccine are not impaired in germ-free or antibiotic-treated mice
Authors: Todd Norton, Miriam Anne Lynn, Charné Rossouw, Arunasingam Abayasingam, Griffith Perkins, Pravin Hissaria, Rowena Anne Bull, David John Lynn
Journal: Gut (2023)
A New In Vitro Blood Flow Model for the Realistic Evaluation of Antimicrobial Surfaces
Authors: Juliane Valtin, Stephan Behrens, André Ruland, Florian Schmieder, Frank Sonntag, Lars D. Renner, Manfred F. Maitz, Carsten Werner
Journal: Advanced Healthcare Materials (2023)

Abstract Device‐associated bloodstream infections can cause serious medical problems and cost‐intensive postinfection management, defining a need for more effective antimicrobial coatings. Newly developed coatings often show reduced bacterial colonization and high hemocompatibility in established in vitro tests, but fail in animal studies or clinical trials. The poor predictive power of these models is attributed to inadequate representation of in vivo conditions. Herein, a new single‐pass blood flow model, with simultaneous incubation of the test surface with bacteria and freshly‐drawn human blood, is presented. The flow model is validated by comparative analysis of a recently developed set of antiadhesive and contact‐killing polymer coatings, and the corresponding uncoated polycarbonate surfaces. The results confirm the model's ability to differentiate the antimicrobial activities of the studied surfaces. Blood activation data correlate with bacterial surface coverage: low bacterial adhesion is associated with low inflammation and hemostasis. Shear stress correlates inversely with bacterial colonization, especially on antiadhesive surfaces. The introduced model is concluded to enable the evaluation of novel antimicrobial materials under in vivo‐like conditions, capturing interactions between bacteria and biomaterials surfaces in the presence of key components of the ex vivo host response.
Stationary-to-migratory transition in glioblastoma stem-like cells driven by a fatty acid-binding protein 7-RXR<b>α</b> neurogenic pathway
Authors: Rong-Zong Liu, Won-Shik Choi, Saket Jain, Xia Xu, Marwa E Elsherbiny, Darryl D Glubrecht, Anthony G Tessier, Jacob C Easaw, B Gino Fallone, Roseline Godbout
Journal: Neuro-Oncology (2023)

Abstract Background Glioblastoma (GBM) stem-like cells (GSCs) are crucial drivers of treatment resistance and tumor recurrence. While the concept of “migrating” cancer stem cells was proposed a decade ago, the roles and underlying mechanisms of the heterogeneous populations of GSCs remain poorly defined. Methods Cell migration using GBM cell lines and patient-derived GSCs was examined using Transwell inserts and the scratch assay. Single-cell RNA sequencing data analysis were used to map GSC drivers to specific GBM cell populations. Xenografted mice were used to model the role of brain-type fatty acid-binding protein 7 (FABP7) in GBM infiltration and expansion. The mechanism by which FABP7 and its fatty acid ligands promote GSC migration was examined by gel shift and luciferase gene reporter assays. Results A subpopulation of FABP7-expressing migratory GSCs was identified, with FABP7 upregulating SOX2, a key modulator for GBM stemness and plasticity, and ZEB1, a prominent factor in GBM epithelial-mesenchymal transition and invasiveness. Our data indicate that GSC migration is driven by nuclear FABP7 through activation of RXRα, a nuclear receptor activated by polyunsaturated fatty acids (PUFAs). Conclusion Infiltrative progression in GBM is driven by migratory GSCs through activation of a PUFA-FABP7-RXRα neurogenic pathway.
European Respiratory Society/American Thoracic Society technical statement: standardisation of the measurement of lung volumes, 2023 update
Authors: Nirav R. Bhakta, Aisling McGowan, Kathryn A. Ramsey, Brigitte Borg, Jana Kivastik, Shandra Lee Knight, Karl Sylvester, Felip Burgos, Erik R. Swenson, Kevin McCarthy, Brendan G. Cooper, Francisco García-Río, Gwen Skloot, Meredith McCormack, Carl Mottram, Charles G. Irvin, Irene Steenbruggen, Allan L. Coates, David A. Kaminsky
Journal: European Respiratory Journal (2023)

This document updates the 2005 European Respiratory Society (ERS) and American Thoracic Society (ATS) technical standard for the measurement of lung volumes. The 2005 document integrated the recommendations of an ATS/ERS task force with those from an earlier National Heart, Lung, and Blood Institute workshop that led to the publication of background papers between 1995 and 1999 and a consensus workshop report with more in-depth descriptions and discussion. Advancements in hardware and software, new research and emerging approaches have necessitated an update to the 2005 technical standard to guide laboratory directors, physiologists, operators, pulmonologists and manufacturers. Key updates include standardisation of linked spirometry, new equipment quality control and validation recommendations, generalisation of the multiple breath washout concept beyond nitrogen, a new acceptability and grading system with addition of example tracings, and a brief review of imaging and other new techniques to measure lung volumes. Future directions and key research questions are also noted.
Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF)
Authors: Mazen Noureddin, Emily Truong, Rebeca Mayo, Ibon Martínez-Arranz, Itziar Mincholé, Jesus M. Banales, Marco Arrese, Kenneth Cusi, María Teresa Arias-Loste, Radan Bruha, Manuel Romero-Gómez, Paula Iruzubieta, Rocio Aller, Javier Ampuero, José Luis Calleja, Luis Ibañez-Samaniego, Patricia Aspichueta, Antonio Martín-Duce, Tatyana Kushner, Pablo Ortiz, Stephen A. Harrison, Quentin M. Anstee, Javier Crespo, José M. Mato, Arun J. Sanyal
Journal: Hepatology (2023)

Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH.
Apoptotic contraction drives target cell release by cytotoxic T cells
Authors: Elisa E. Sanchez, Maria Tello-Lafoz, Aixuan J. Guo, Miguel de Jesus, Yassmin A. Elbanna, Benjamin Y. Winer, Sadna Budhu, Eric Chan, Eric Rosiek, Taisuke Kondo, Justyn DuSold, Naomi Taylor, Gregoire Altan-Bonnet, Michael F. Olson, Morgan Huse
Journal: Nature Immunology (2023)
Authority of Medicare to Limit Coverage of FDA-Approved Products
Authors: C. Joseph Ross Daval, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2023)

When the US Food and Drug Administration (FDA) approves a drug or medical device on the basis of limited clinical evidence, the Centers for Medicare & Medicaid Services (CMS) must decide whether the therapy is "reasonable and necessary" for coverage among Medicare beneficiaries. However, the legal underpinnings of CMS's authority to shape coverage of FDA-regulated products under Medicare Part B are controversial. To clarify this area, we reviewed relevant legal precedents on CMS's approaches to limit coverage and recent decisions Medicare has issued affecting coverage for FDA-regulated products.The CMS continues to exercise considerable legal discretion to limit coverage of FDA-authorized products to only uses it determines are reasonable and necessary for patients with Medicare. Courts have upheld this discretion repeatedly, emphasizing the difference between Medicare's coverage criteria and the FDA's review standards. As more new drugs and devices come to market without solid evidence of efficacy on clinical outcomes, or have narrow benefit-risk considerations, CMS may increasingly rely on forms of limited or conditional coverage, including coverage with evidence development (CED), which provides reimbursement only in the context of a clinical trial or registry.The ability of CMS to condition or limit coverage of FDA-approved products is a commonsense necessity for this crucial taxpayer-funded program. Although courts have thus far deferred to the authority of CMS to make such decisions on the basis of its clear statutory discretion and public health expertise, Congress may want to act to reaffirm statutory language giving CMS sufficient flexibility to craft coverage determinations that reflect the evidence for a product's use.